Cystinosis has been known since the first decade of the last century. Small, pale children who died of wasting and whose organs were shown to be riddled with microscopic crystals were described by Abderhalden in 1903. He termed the condition “Familiare Cystindiathese” (Thoene. Mol Genet Metab. 2007, herein incorporated by reference in its entirety). The disease has been conflated with the unrelated condition cystinuria, which is an extracellular disease of renal transport which results in excess cystine urinary excretion, leading to cystine stones in the urinary tract (Palacin et al., eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edition, McGraw Hill, 4909-4932, 2001, herein incorporated by reference in its entirety), while cystinosis is an intracellular condition that results from defective lysosomal cystine transport, leading to lysosomal cystine storage. The lysosomal cystine transporter, cystinosin, is encoded by CTNS, located at 17 p 13.3, and functions to move cystine from the lysosomal interior to the cytosol, where it can be reused for GSH and protein synthesis. Many mutations have been described at this locus, however a large 57 kb deletion accounts for about half the cases descended from west European parents. The clinical phenotype in nephropathic cystinosis is relatively unique: renal Fanconi syndrome with salt, water, glucose, amino acid and other small molecule losses; crystalline keratopathy and salt and pepper retinopathy; short stature and failure to thrive; photophobia; and ultimately renal death by age 10 years. Other elements include hypothyroidism, and later in life, muscle weakness, esophageal dysmotility, and diabetes. It produces the renal Fanconi syndrome with salt, water and other small molecule wasting, deficient bone mineralization, short stature, failure to thrive, and later in life, hypothyroidism, muscle wasting and weakness, esophageal dysmotility, pancreatic deficiency, and pulmonary involvement. It is treated symptomatically with salt and water replacement, and specifically, with cysteamine, which causes depletion of the stored lysosomal cystine which is the biochemical hallmark of the condition and which results from mutations in the lysosomal cystine transporter, cystinosin. Therapy of cystinosis has taken several forms, although none is currently satisfactory. Initially recognition of the peril these children are in from the risk of dehydration and electrolyte imbalance led to symptomatic water and electrolyte replacement therapy. Subsequently, chronic dialysis and then renal transplantation were used to compensate for the renal failure. Specific therapy for cystinosis was achieved in 1994 when the FDA approved cysteamine bitartrate as Cystagon for the treatment of cystinosis. This drug causes depletion of cystine from cystinotic lysosomes by forming a mixed disulfide with cystine which resembles lysine and which can thus exit lysosomes on the intact lysine transporter. Unfortunately, the structure of cysteamine includes a free thiol group, thus the drug has the odor and taste of rotten eggs, a feature of concern both to parents administering the treatment to children, and to patients themselves who may find the offensive odor to be socially debilitating. Although cysteamine has been FDA approved since 1994, there are problems with this therapy: 1) It does not prevent renal failure, but merely delays the onset, for most patients 2) its repugnant thiol odor and taste causes both gastrointestinal and compliance problems and social concerns in children as they reach adolescence. The latter issue causes some patients to forgo or discontinue treatment, with the expected concomitant health consequences resulting therefrom. For these reasons, a superior form of treatment that averts renal failure indefinitely, and which lacks the thiol odor and taste of cysteamine would be highly desirable.
Gene therapy has been proposed to treat a variety of conditions, including inborn errors of metabolism, however serious reactions to AV and AAV vectors has lead to questioning in the field as whether these agents can be safely employed in patients. Gene therapy, long the hope of patients with many diseases, both genetic and otherwise, has continuing issues of safety and efficacy. The safety concerns relate to integration of the trans genes in locations that disrupt the function of critical tumor supressors, or other vital sequences. Other side effects include serious or fatal allergic reactions to the large number of virions which must be administered in the quest for stable gene expression that will have a salutary impact on phenotype. A death was reported in July, 2007 in an arthritis patient receiving gene therapy using an AAV vector, which was hoped to be safer than the AV vector involved in the Geissinger death in 1999.